Mitochondrial Deletions in Mood Disorders Mood disorders (bipolar disorder, BD; major depressive disorder, MDD) account for a high percentage of life- time disability on a world-wide basis, shortened life span, and devastating personal impacts. The pathophysiology of mood disorders, implicates major abnormalities in energy metabolism and mitochondrial function. Mitochondrial dysfunction and disease can be inherited from genetic mutation and can affect multiple target organs, including the brain. We believe that part of the risk for developing mood disorders is genetic variation involving mitochondria DNA (mtDNA). We have replicated our initial findings that a large common somatic deletion of 4,977 base pairs of mtDNA is increased in mood disorders compared to controls. It is important to note that these large deletions of mtDNA appear more frequently in tissues with high metabolic rates, such as brain and muscle and accumulate in an age dependent manner. We believe the study of the full spectrum of large deletions and possible translation into protein will provide substantial evidence supporting the role of mitochondrial dysfunction in mood disorders. In this proposal we hypothesize that large somatic mtDNA deletions accumulate in brain to high levels in mood disorders leading to abnormalities in mitochondrial function. We propose three Specific Aims focusing on the accumulation of large deletions in MDD and BD. 1) Collect fresh mitochondria from human brain (10 MDD, 10 BD, and 10 controls) from which we will sample fourteen brain regions implicated in cognition, affective regulation, and anhedonia in mood disorders. 2) Generate a spectrum of large deletion sequences in mtDNA and cDNA in human brain. 3) Determine the impact of large deletion sequences on proteins and on mitochondria function. We have already discovered novel large somatic mtDNA deletions in postmortem human brains, and are now ready to screen the full spectrum of mtDNA deletions that might cause mitochondrial dysfunction in psychiatric disorders. These novel deletions occur in brain samples at even higher levels compared to the known common deletion of mtDNA. Currently, there are no reports of either protein translation or functional effects of these large deletions i human brain. In the interest of collaborative research, we will share all mtDNA deletion sequences at NCBI. These results could lead to novel treatments that target mitochondrial functional deficits and reduce the accumulation of somatic deletions, thereby improving therapy of mood disorders.